Non-steroid hormonal agents



United States Patent "ice 3,506,653 NON-STEROID HORMONAL AGENTS John H.Fried, Palo Alto, Calif., assignor to Syntex Corporation, Panama,Panama, a corporation of Panama No Drawing. Filed Sept. 12, 1966, Ser.No. 578,442 Int. Cl. C07c 15/24 US. Cl. 260-240 13 Claims The presentinvention relates to novel compounds possessing pharmacologicalproperties associated with steroidal hormonal agents. The newnon-steroidal hormonal agents are benzylidene derivatives of aromaticcompounds containing two fused rings. More particularly, these agentsare benzylidene and p-substituted benzylidene derivatives ofl-(2H)-3,4-dihydronaphthalene. The compounds of the present inventionare represented by the following formula:

wherein R is hydrogen, hydroxy, lower alkoxy, cycloalkoxy,2-dialkylaminoethoxy, 2-piperidinoethoxy, 2-pyrrolidinoethoxy,2-morpholinoethoxy or tetrahydropyran-2-y1oxy;

R is hydrogen, lower alkyl, chloro or fluoro;

each of R and R independently is hydrogen or lower alkyl; and

R is hydrogen, hydroxy, lower alkoxy, cycloalkoxy, 2-dialkylaminoethoxy, 2-piperidinoethoxy, Z-pyrrolidinoethoxy,2-morpholinoethoxy or tetrahydropyran-2- yloxy.

By the term lower alkoxy is meant a straight chain carbon atom groupcontaining from 1 to 4 carbon atoms, inclusive, such as methoxy, ethoxy,propoxy and butoxy. By the term cycloalkoxy is meant a saturated ringcarbon group containing 5 or 6 carbon atoms, such as cyclopentyloxy andcyclohexyloxy. By the term alkyl in 2-dialkylaminoethoxy is meant astraight chain carbon atom group containing from 1 to 4 carbon atomsinclusive. Thus, Z-dialkylaminoethoxy includes 2-dimethylaminoethoxy,Z-diethylaminoethoxy, 2-dipropylaminoethoxy and 2-dibutylaminoethoxy.

The novel compounds of the present invention are prepared by thefollowing process:

(II) (I a R I Rl a wherein all substituents are as previously definedherein- 3,506,653 Patented Apr. 14, 1970 naphthalenone of Formula II andthe Wittig reagent of Formula III are refluxed in a high boiling, inertorganic solvent such as xylene, diphenyl ether, diethyleneglycoldimethyl ether, triethyleneglycol dimethyl ether or the like for aperiod of about twenty-four hours to afford the novel compounds ofFormula I.

Alternatively, the R and R substituents, in a compound of Formula I, aslower alkoxy, cycloalkoxy, 2- dialkylaminoethoxy, 2-piperidinoethoxy,2-pyrroliclinoethoxy, 2-morpholinoethoxy or tetrahydropyran-2-yloxy, areintroduced subsequent to the above reaction of the present invention viaconventional techniques by treating the corresponding compound ofFormula I, wherein R and/or R are hydroxy, with an appropriate reagent.For example, a lower alkoxy or cycloalkoxy substituent is introduced bytreatment of the hydroxy compound with sodium or potassium carbonate inacetone followed by the addition of the alkoxy or cycloalkoxy halide,preferably the chloride. A 2-dialkylaminoethoxy, Z-piperidinoethoxy,2-pyrrolidinoethoxy, or a 2-morpholinoethoxy substituent is introducedby treatment of the hydroxy compound with B-chloroethylamine in methanolcontaining sodium methoxide. Thus, the alkylation of the hydroxycompound is effected by treating the sodium salt withB-chloroethyldialkylamine, B-chloroethylpiperidine,B-chloroethylpyrrolidine, or ,B-chloroethylmorpholine, respectively. ThetetrahydropyramZ-yloxy substituent is introduced by treating acorresponding hydroxy compound with dihydropyran in the presence of aninert solvent such as p-toluenesulfonic acid or p-toluenesulfonilchloride in an inert solvent such as benzene.

Alternatively, the novel compounds of the present invention are preparedby the following process:

wherein X is chloro or bromo;

R is hydrogen, lower alkoxy, cycloalkoxy, 2-dialkylaminoethoxy,Z-piperidinoethoxy, 2-pyrrolidinoethoxy 2-morpholinoethoxy, ortetrahydropyran-2'-yloxy; and

all other substituents are as previously defined.

In carrying out the alternative process, a 3,4-dihydronaphthalenone ofFormula II is reacted with a Grignart reagent of Formula IV in an inert,anhydrous solvent such as tetrahydrofuran, diethyl ether or the like toafford a novel tertiary carbinol intermediate of Formula V. The carbinolintermediate of Formula V is then dehydrated by treatment with thionylchloride in pyridine at room temperature for a period of about one hourto afford the novel compounds of Formula VI of the present invention.

Alternatively, the R substituent, in a compound of Formula VI, as loweralkoxy, cycloalkoxy, 2-dialkylaminoethoxy, 2 piperidinoethoxy,2-pyrrolidinoethoxy, 2- morpholinoethoxy, or tetrahydropyran-2-yloxy, isintroduced subsequent to the above second process of the presentinvention via conventional techniques by treating the correspondingcompound of Formula VI wherein R is hydroxy with an appropriate reagentas described hereinabove.

The novel compounds of Formula I demonstrate estro genic andanti-estrogenic activities. Those compounds of Formula I, wherein eitherR R or both R and R is Z-dialkylaminoethoxy, 2-pyrrolidinoethoxy,2-piperidinoethoxy or 2-morpholinoethoxy, have pronounced antiestrogenicactivity and are useful as anti-fertility agents, for lowering bloodcholesterol levels and for inhibiting steroidal biosynthesis. Thosecompounds of Formula I, wherein either R R or both R and R is hydrogen,hydroxy, lower alkoxy, cycloalkoxy, or tetrahydropyran- 2-yloxy haveestrogenic activity and are useful in causing weight gains in animalsand treatment of uterine dis orders. The novel hormonal agents of thepresent invention are administered via usual routes, i.e. orally orparenterally in pharmaceutically acceptable compositions at dosage ratesof from 0.5 to mg./kg./day. However, dosage rates below or above thisrange can also be used; the most favorable dosage rate andadministration route being conditioned upon the purpose for which it isadministered and the response thereto.

The novel compounds of Formula V are useful as intermediates in thepreparation of the non-steroidal hormonal agents of the presentinvention.

Illustrative of the starting materials of Formula II for the process ofthis invention are the following 1- (2H -3 ,4-dihydronaphthalenones,namely 3 ,4-dihydronaphthalenone;

3 ,4dihydro-5-chloro-6-methoxynaphthalenone;3,4-dihydro-7-chloro-6-methoxynaphthalenone;

3 ,4-dihyd r0-5fluoro-6-methoxynaphthalenone;3,4-dihydro-7-fiuoro-6-methoxynaphthalenone;

3 ,4-dihydro-6-hyd roxynaphthalenone;

3 ,4-dihydro-6-methoxy-2-p ropylnaphthalenone;3,4-dihydro-6-(tetrahydropyran-Z-yl)-oxynaphthalenone; 3,4-dihydro-3-methylnaphthalenone;

3 ,4-dihyd ro-S-methylnaphthalenone; 3,4-dihydro-7-methylnaphthalenone;3,4-dihydro-3-methyl-2-propylnaphthalenone; and 3 ,4-dihydro-7-propylnaphthalenone.

The starting materials of Formula II, wherein R is lower alkoxy orcycloalkoxy, are prepared from a corresponding hydroxy compound, i.e.Formula II, wherein R is hydroxy, by the alkylation procedure asdescribed hereinabove. The starting materials of Formula II, wherein Ris Z-dialkylaminoethoxy, Z-piperidinoethoxy, 2-pyrrolidinoethoxy orZ-morpholinoethoxy, are prepared from a corresponding hydroxy compound,i.e. Formula II, wherein R is hydroxy, by an alkylation procedure asdescribed hereinabove. The starting materials of Formula II, wherein Ris tetrahydropyran-2'-yloxy are prepared from a corresponding hydroxycompound as described hereinabove by treatment with dihydropyran in thepresence of an acid catalyst, such as p-toluenesulfonic acid orp-toluenesulfonyl chloride, in an inert solvent, such as benzene.

The Wittig reagents of Formula III are prepared according toconventional procedures, such as (Trippett, 5., Advances in OrganicChemistry, vol. I, pp. 83-102; Trippett, S. Quarterly Reviews, vol.16-17, pp. 406-440 (1962- 1963), and Greenwald, R., Chaykovsky, M., andCorey, E. J., J. Org. Chem, 28, 1128-1129 (1963)). Similarly,

the Grignard reagents of Formula IV are prepared via conventionalprocedures known to those skilled in the art.

The following examples serve to illustrate but are not intended to limitthe scope of the present invention.

PREPARATION A p-Bromomethylphenol To 15 ml. of glacial acetic acid isadded 4.7 g. of phenol and 3.5 g. of paraformaldehyde. The mixture iscooled to 0 C. and anhydrous hydrogen bromide is passed into thereaction mixture until the solution is saturated. During the addition,heat is evolved, and the rate is controlled so that the temperature ofthe mixture does'not exceed C. Near the saturation point, the suspendedparaformaldehyde disappears and a clear solution results. The saturatedsolution is cooled and the reaction product precipitates from thesolution. The solid product is filtered and recrystallized from heptaneto yield p-brom o'methylphenol.

PREPARATION B Ether preparation To a solution of 4.7 g. of phenol in ml.of ethanol was added 22.4 g. of 25% sodium methoxide in methanol. After10 minutes, 16.1 g. of N-(2-chloroethyl)- piperidine (obtained byneutralization of the corresponding hydrochloride) in 100 ml. of ethanolis added to the mixture. The mixture is refluxed for a period of 16hours, cooled and filtered. The filtrate is concentrated in vacuo, takenup in ether and washed with water. After removing the ether, the residueis distilled through a short Vigreux column to yield phenylZ-piperidinoethyl ether.

Utilizing the above procedure with one exception, namely substituting anequivalent amount of N-(Z-chloroethyl)-pyrrolidine, N(Z-chloroethyl)-morpholine, and 1 diethylamino-2-chloroethane for theabove N- (2- chloroethyl)-piperidine, there are obtained thecorresponding phenyl Z-pyrrolidinoethyl ether, phenyl 2-morpholinoethylether and Z-diethylaminoethyl ether, respectively. The above1-diethylamino-2-chloroethane is prepared according to the procedure ofBreslow et al., J. Am. Chem. Soc., 76, 1472 (1945).

PREPARATION C Bromo and chloromethylation procedures To 15 ml. ofglacial acetic acid is added 4.7 g. of anisole and 3.5 g. ofparaformaldehyde. The mixture is cooled to 0 C. and anhydrous hydrogenbromide is passed into the reaction mixture until the solution issaturated. During the addition, heat is evolved, and the rate iscontrolled so that the temperature of the mixture does not exceed 80 C.Near the saturation point, the suspended paraformaldehyde disappears anda clear solution results. The saturated solution is cooled and thereaction product precipitates from solution. The solid product isfiltered and recrystallized from heptane to yield p-bromomethylanisole.

Utilizing the same procedure with one exception, namely replacinganisole with each of the following ethers, namely phenyl cyclopentylether;

phenyl diethylaminoethyl ether; phenyl morpholinoethyl ether; and phenylpiperidinoethyl ether;

there are obtained the corresponding p-bromomethyl compounds, namelyp-bromomethylphenyl cyclopentyl ether;

p-bromomethylphenyl 2-diethylaminoethyl ether;

p-bromomethylphenyl 2-morpholinoethyl ether; and

p brcimomethylphenyl 2 piperidinoethyl ether, respectrve y.

Utilizing the same procedure with one exception, namely substitutinghydrogen chloride for hydrogen bromide in the above method, there areobtained the corresponding p-chloromethyl phenyl ethers.

PREPARATION D 2-dialkylaminoethoxy and Z-piperidinoethoxy startingmaterials A solution of 3 g. of 6-hydroxy-3,4-dihydronaphthalenone and 2g. of potassium carbonate in 50 ml. of

Chloro compound Final products ,B-chloroethylpiper-6-(2-piperidino)-ethoxyidine. 3,4-dihydronaphthalenone.

6- (2-dibutylaminoethoxy) 3 ,4-dihydronaphthalenone.

6- (Z-dimethylaminoethoxy) -3,4-dihydronaphthalenone.

PREPARATION E 5 and 7 halo-1(2H)-3,4-dihydronaphthalenone A mixture of 5g. of 6-methoxy-1(2H)-naphthalenone in 50 ml. of water and 5 ml. ofconcentrated sulfuric acid is cooled to 0 C. Fifteen milliliters ofconcentrated nitric acid is added dropwise while the temperature ismaintained below 20 C. The mixture is held at 20 C. for a period of 30minutes and then poured over 50 ml. of cracked ice. The product isseparated by filtration, chromatographed on neutral alumina andrecrystallized from ethanolzethyl acetate to yield S-nitro-6-methoxy-1(2H)-naphthalenone and 7 nitro 6 methoxy-1(2H)- napthalenone.

A mixture of 2 g. of 5-nitro-6-methoxy-l(2H)-naphthalenone in 50 ml. ofwater and 5 ml. of concentrated hydrochloric acid is allowed to reactwith 5 g. of metallic tin. The reaction mixture is held at 25 C. for aperiod of four hours. At the end of the reaction, the mixture isfiltered to remove inorganic salts and the aqueous solution is extractedwith ether. The ether extract is dried and evaporated to yield 5 amino 5meth0xy-1(2H)- naphthalenone.

In a similar fashion, the 7-nitro-6-methoxy-1(2H)- naphthalenone isconverted to 7-amino-6-methoxy-l(2H)- naphthalenone.

A solution of 5 g. of 5-amino-6-methoxy-1(2H)- naphthalenone and 25 ml.of concentrated hydrochloric acid is allowed to react with 3 g. ofsodium nitrite in 20 ml. of water. The reaction mixture is allowed tostand for three hours at 0 C. Cuprous chloride in 20 ml. of concentratedhydrochloric acid is added to the solution. The reaction mixture iswarmed for /2 hour at 50 C. The aqueous phase is extracted with etherand the ether extract is dried and evaporated to dryness to yield 5-chloro-6-methoxy 1(2H)-naphthalenone.

In a similar fashion, the 7-amino-6-methoxy-1(2H)- naphthalenone isconverted to the corresponding 7-chloro- 6-methoxy-1(2H)-naphthalenone.

A cold solution of 3 g. of 5-arnino-6-methoxy-l (2H)- naphthalenone inml. of 40% fluoroboric acid is diazol-dibutylamino-Z- chloropropane.

1-dimethylamino-2- chloropropane.

tized by the addition of 3 g. of sodium nitrite, and the solid beingadded in portions. The temperature of the reaction mixture is maintainedbelow 10 C. during this addition. The reaction mixture is then allowedto stand at 10 C. for one hour, and is then warmed to 50 C. for /2 hour.The reaction mixture is poured into 50 ml. of ice water and the aqueousphase is extracted with ether. The ether extract is dried and evaporatedto dryness to yield 5-fluor-o-6-methoxy-l(2H)-naphthalenone.

In a similar fashion, the 7-amino-6-methoxy-1(2H)- naphthalenone isconverted to the corresponding 7-fluoro- 6-methoxyl (2H)-naphthalenone'.

EXAMPLE 1 l-(benzylidene) analogs To a solution of 10 g. oftriphenylphosphine in 50 ml. of benzene is added 9 g. of benzylbromide.The reaction mixture is allowed to stand at room temperature for twohours and the solid material is filtered and Washed with benzene toyield benzyltriphenylphosphonium bromide. A mixture of 4 g. of thebenzyltriphenylphosphonium bromide and 1 g. of phenyllithium in 40 ml.of anhydrous tetrahydrofuran is allowed to stand at 25 C. for a periodof three hours. The tetrahydrofuran is removed by evaporation underreduced pressure and replaced with 40 ml. of xylene. To this mixture isadded 1.5 g. of 6-hydroxy- 3,4-dihydronaphthalenone and the reactionmixture is heated at reflux for 24 hours, then cooled and reduced todryness under reduced pressure. The residue is Washed with water,extracted with ether; the extract is dried and evaporated to dryness toyield 1-benzylidene-6-hydroxy- 3,4-dihydronaphthalene which isrecrystallized from ethyl acetatezpetroleum ether.

Utilizing the same procedure, the following starting materials, namely5-chloro-6-methoxy-3 ,4-dihydronaphthalenone; 7-chloro-6-methoxy-3,4-dihydronaphthalenone; 7-fluoro-6-methoxy-3,4-dihydronaphthalenone;and 5-fluoro-6-rnethoxy-3,4-dihydronaphthlenone;

are converted to the corresponding l-(benzylidene) analogs, namely 1benzylidene 5 chloro-6-methoxy-3,4-dihydronaphthalene;

1 benzylidene 7 chloro-6-methoxy-3,4-dihydr0naphthalene;

1 benzylidene 7 fluoro-6-methoxy-3,4-dihydronaphthalene; and

1 benzylidene 5 fluoro-6-methoxy-3,4-dihydronaphthalene, respectively.

EXAMPLE 2 l-(p-hydroxybenzylidene) analogs To a solution of 10 g. oftriphenylphosphine in 50 ml. of benzene, is added 10 g. ofp-bromomethylphenol. The reaction mixture is allowed to stand at roomtemperature for two hours and the solid material is filtered and washedwith benzene to yield p-hydroxybenzyltriphenylphosphonium bromide. Amixture of 4 g. of the p-hydroxybenzyltriphenylphosphonium bromide and 3g. of sodium eth oxide in 40 ml. of dimethylformamide is allowed tostand for three hours. The dimethylformamide is removed by evaporationunder pressure and replaced with 40 ml. of xylene. To this mixture isadded 1.5 g. of 6-hydroxy-3,4- naphthalenone and the reaction mixture isheated at reflux for 24 hours, then cooled and reduced to dryness underreduced pressure. The residue is washed with water, extracted withether; the extract is dried and evaporated to dryness to yieldl-(p-hydroxybenzylidene)-6-hydroxy- 3,4-dihydronaphthalenone which isrecrystallized from ethyl acetatezpetroleum ether.

Utilizing the same procedure, the following starting materials, namely-chloro-6-methoxy-3 ,4-naphthalenone;

7 -chloro-6-methoxy-3 ,4-dihydronaphthalenone;7-chloro-6-methoxy-3,4-naphthalenoue; and

5 -fluoro-6-methoxy-3 ,4-dihydronaphthalenone;

are converted to the corresponding l-(p-hydroxybenzylidene) analogs,namely l-(p-hydroxybenzylid ene) -5-chloro-6-methoxy-3 ,4-

dihydronaphthalene;

1-( p-hydroxybenzylidene)-7-chloro-6-methoxy-3,4-

dihydronaphthalene;

1-( p-hydroxybenzylidene)-7-chloro-6-methoxy-3,4-

dihydronaphthalene; and

l-(p-hydroxybenzylidene)-5-fluoro-6-methoxy-3,4-

dihydronaphthalene, respectively.

EXAMPLE 3 Z-dialkylaminoethoxy and 2-pyrrolidinoethoxybenzylideneanalogs To a solution of 3 g. of6-methoxy-l-(p-hydroxybenzylidene)-3,4-dihydronaphthalenone and 2 g. ofpotassium carbonate in 50 ml. of acetone is added 2 g. ofl-diethylamino-Z-chloroethane (prepared according to the procedure ofBreslow, et al., J. of Am. Chem. Soc., 67, 1472 (1945)). The reactionmixture is heated at reflux for a period of 24 hours, cooled andevaporated to dryness. The residue is recrystallized from ethylacetatezbenzene to yield 1 (2-diethylaminoethoxy)benzylidene-6-methoxy-3,4-dihydronaphthalene.

Utilizing the same procedure with one exception, namely substituting amolar equivalent, each of the following amines (prepared according tothe procedure of Breslow, et al., J. of Am. Chem. Soc., 67, 1472(1945)), namely 1-dimethylamino-2-chloroethane; and

1 dibutylamino 2 chloroethane, there are obtained the correspondingdialkylaminoethoxy final products, namely 1- (Z-dimethylaminoethoxy)-benzylidene-6-methoxy-3 ,4-

dihydronaphthalene; and

1-(2-dibutylaminoethoxy)-benzylidene-6-methoxy-3,4-

dihydronaphthalene, respectively.

In a similar fashion, by using the same procedure and starting materialand substituting fi-chloroethylpyrrolidine for the above1-diethylamino-2-chloroethane, there is obtained the corresponding2-pyrrolidinoethoxy compound, namely 1- (Z-pyrrolidinoethoxy)-benzylidene-6-methoxy-3,4-

dihydronaphthalene.

EXAMPLE 4 Grignard preparation A solution of 5 g. of6-methoxy-3,4-dihydronaphthalenone in 250 ml. of thiophene-free benzeneis treated with an equimolar amount of benzylmagnesium bromide inanhydrous ether. The mixture is heated at reflux under anhydrousconditions for three hours, cooled and cautiously treated with an excessof aqueous ammonium chloride solution. This mixture is extracted withexcess ammonium chloride solution. This mixture is then extracted withethyl acetate and these extracts are in turn washed with water, driedover sodium sulfate and evaporated to dryness to yield1-benzylidene-6-methoxy-3,4-dihydronaphthalene which is recrystallizedfrom ethyl acetatetpetroleum ether.

Utilizing the above procedure,

7 chloro 6-methoxy-3,4-dihydronaphthalenone is converted to1-benzylidene-7-chloro-6-methoxy-3,4-dihydronaphthalene.

8 EXAMPLE 5 tetrahydropyran-2'-yl ethers To a slurry of 1.0 g. of sodiumhydride in 10 ml. of dry diethyleneglycol dimethyl ether under a drynitrogen atmosphere is slowly added 1.0 g. of l-(p-hydroxybenzybidene)-6-hydroxy-3,4-dihydronaphthalene in 10 ml. of drydiethyleneglycol dimethyl ether in a dropwise fashion over a 20 minuteperiod. To this mixture is added drop wise, 0.9 g. of2-chlorotetrahydropyran over a 10 minute period.

The mixture is stirred at room temperature for an ad ditional 30 minutesand then cautiously added to an icewater mixture with stirring. Theorganic phase is extracted with diethyl ether, dried and evaporatedunder reduced pressure to yield1-[p-(tetrahydropyran-2-yloxy)-benzylidene] 6(tetrahydropyran-2'-yloxy)-3,4- dihydronaphthalene which may be furtherpurified via recrystallization from acetonezhexane.

EXAMPLE 6 alkyl and cycloalkyl ethers A solution of one equivalent of1-benzylidene-6-hydroxy-3,4-dihydronaphthalene in 30 ml. of benzene isheated to reflux and about 2 ml. removed by distillation to eliminatemoisture. The mixture is cooled to room temperature and two equivalentsof sodium hydride are added, followed by the dropwise addition of twoequivalents of cyclopentyl bromide in 10 ml. of benzene over a period of20 minutes. The mixture is allowed to reflux for 20 hours after whichtime the precipitate of sodium bromide is removed by filtration and theorganic phase dried and evaporated to yield1-benzylidene-6-cyclopentyloxy-3,4-dihydronaphthalene which is furtherpurified upon recrystallization from pentane.

Utilizing the above procedure and starting materials but substituting amolar equivalent of methyl chloride for cyclopentyl bromide, there isobtained the corresponding methyl ether, namely1-benzylidene-6-methoxy-3,4-dihydronaphthalene.

EXAMPLE 7 Wittig reactionmethylsulfinyl carbanion method To a mixture of1 g. of sodium hydride in 20 ml. of pentane under an inert atmosphere,is slowly added 50 m1. of dimethylsulfoxide and the reaction mixture isheated at 7580 C. for minutes and then cooled to afford a solution ofmethylsulfinyl carbanion. To this solution is added 17 g. ofbenzylidenetriphenylphosphonium bromide and 40 ml. of dimethylsulfoxideand the mixture is held at room temperature for 10 minutes. The solventis then removed by evaporation under reduced pressure and replaced with40 ml. of xylene. To this mixture is added 8 g. of6-hydroxy-3,4-dihydronaphthalenone and the resulting mixture is allowedto stir at room temperature for an additional 30 minutes. The reactionmixture is then poured into ml. of ice water and extracted with ether.The organic phase is washed with water, dried and evaporated to drynessand recrystallized from ethyl acetatezpetroleum ether to yield1-benzylidene-6-hydroxy-3,4-dihydronaphthalene.

EXAMPLE 8 Bis ethers A solution of one equivalent ofl-(p-hydroxybenzylidene)-6-hydroxy-3,4-dihydronaphthalene in 30 ml. ofbenzene is heated to reflux and about 2 ml. removed by distillation toeliminate moisture. The mixture is cooled to room temperature and twoequivalents of sodium hydride are added, followed by the addition of twoequivalents of methyl chloride in 10 ml. of benzene over a period of 20minutes. The mixture is allowed to reflux for 20 hours after which timethe precipitate of sodium chloride is removed by filtration and theorganic phase dried and evaporated to yieldl-(p-methoxybenzylidene)-6-methoxy- 3,4-dihydronaphthalene which isfurther purified upon recrystallization from pentane.

Utilizing the above procedure, the same starting material is alkylatedwith the indicated chloro compounds to afford the following finalproducts:

Chloro compound: Final product 1 dimethylamino 2- l-[p (2dimethylaminochlorethane. ethoxy) benzylidene1-6-(2'-dimethylaminoethoxy)- 3,4-dihydronaphthalene. Bchloroethylpyrrolil-[p (2-pyrrolidinoethoxy)- dine. benzylidene] 6(2'-pyrrolidinoethoxy) 3,4-dihydronaphthalene.

EXAMPLE 9 Bis piperidinoethoxy ethers To a solution of 10 g. oftriphenylphosphine in 50 ml. of benzene is added 10 g. ofp-bromomethylphenyl-Z-piperidinoethyl ether. The reaction mixture isallowed to stand at room temperature for two hours and the solidmaterial is filtered and washed with benzene to yield p-(2-piperidinoethoxy -benzyltriphenylphosphonium bromide. A mixture of 4g. of the latter phosphonium bromide and 1 g. of phenyl lithium in 40ml, of anhydrous tetrahydrofuran is allowed to stand at 25 C. for aperiod of three hours. The tetrahydrofuran is removed by evaporationunder reduced pressure and replaced with 40 ml. of xylene. To thismixture is added 6-(2'-piperidinoethoxy)-3,4-dihydronaphthalenone andthe reaction mixture is heated at reflux for 24 hours, cooled andreduced to dryness under reduced pressure. The residue is washed withwater, extracted with ether; the extract is dried and evaporated todryness to yield 1-[p-2'-piperidinoethoxy)- benzylidene] -6-(2'piperidinoethoxy) 3,4-dihydronaphthalene.

EXAMPLE 10 Bis 2-dialkylam1noethoxy ethers To a solution of 10 g. oftriphenylphosphine in 50 ml. of benzene is added 10 g. ofp-bromomethylphenyl 2-dimethylaminoethyl ether. The reaction mixture isallowed to stand at room temperature for two hours and the solidmaterial is filtered and washed with benzene to yield p-2-dimethylaminoethoxy -benzyltriphenylphosphonium bromide. A mixture of4 g. of the latter phosphonium bromide and 1 g. of phenyl lithium in 40ml. of anhydrous tetrahydrofuran is allowed to stand at 25 C. for aperiod of three hours. The tetrahydrofuran is removed by evaporationunder reduced pressure and replaced with 40 ml. of xylene. To thismixture is added 6-(2-dimethylaminoethoxy)-3,4-dihydronaphthalenone andthe reaction mixture is heated at reflux for 24 hours, cooled andreduced to dryness under reduced pressure. The residue is washed withwater, extracted with ether; the extract is dried and evaporated todryness to yield 1-[p-(2-dimethylarninoethoxy) benzylidene]6-(2'-dimethylaminoethoxy)-3,4- dihydronaphthalene.

1 0 What is claimed is: 1. A compound of the following formula:

wherein R is hydrogen, hydroxy, lower alkyloxy, cyclo- :alkoxy, 2-dialkylaminoethoxy, Z-piperidinoethoxy, 2- pyrrolidinoethoxy,2-morpholinoethoxy or tetrahydropyran-2 yl0xy;

R is hydrogen, lower alkyl, chloro or fiuoro;

each of R and R independently is hydrogen or lower alkyl; and

R is hydroxy, lower alkyloxy, cycloalkoxy, 2-dialkylaminoethoxy,2-piperidinoethoxy, 2-pyrrolidinoethoxy, 2-morpholinoethoxy ortetrahydropyran-2--yloxy.

2. A compound according to claim 1 wherein each of R and R is hydrogen;and R is hydrogen or methyl.

3. A compound according to claim 1 wherein R is 7-chloro or 7-fluoro;and each of R and R is hydrogen.

4. A compound according to claim 1 wherein R is S-chloro or 5-fluoro;and each of R and R is hydrogen.

5. A compound according to claim 2 wherein each of R and R is methoxy;and R is hydrogen.

6. A compound according to claim 2 wherein each Of R and R isZ-dimethylaminoethoxy; and R is hydrogen.

7. A compound according to claim 2 wherein each of R and R is2-pyrrolidinoethoxy; and R is hydrogen.

8. A compound according to claim 2 wherein R is methoxy; R is hydrogen;and R is Z-dimethylaminoethoxy.

9. A compound according to claim 2 wherein R is methoxy; R is hydrogen;and R is 2-pyrrolidinoethoxy.

10. A compound according to claim 2 wherein R is 2-pyrrolidinoethoxy; Ris hydrogen; and R is methoxy.

11. A compound according to claim 2 wherein R is Z-dimethylaminoethoxy;R is hydrogen; and R is me aminoethoxy.

12. A compound according to claim 2 wherein R is Z-dimethylaminoethoxy;R is hydrogen; and R is methoxy.

13. A compound according to claim 2 wherein R is 2- dimethylaminoethoxy;R is hydrogen; and R is 2-pyrrolidinoethoxy.

References Cited US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 506,653 Dated April 14, 1970 Inventor(s) John H. Fried It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

[- Column 1, lines 18 through 24-, Formula (I) should appear as follows:

Column 10, lines 3 though 9, formula in Claim 1 should appear asfollows:

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 506,653 Dated April 14, 1970 Inventor(s) John H. Fried It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 10, line 11, "2'-dialkylaminoethoxy" should read--2-dialkylaminoethoxy.

Column 10, line 41, "dimethylaminoethoxy" should read-pyrrolidinoethoxy.

Column 10, lines 41 and 42, "meaminoethoxy" should read'--dimethylaminoethoxy-.

Signed and sealed this 10th day of November 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

1. A COMPOUND OF THE FOLLOWING FORMULA: